CONTENT

Phosphonates

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o
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Basic properties
Production
Biphosphonates
Uses

Phosphonates Compounds
Editronic Acid
o Synthesis
o Uses
o Properties

Process for manufacturing 1-hydroxyethane 1,1-diphos-phonic acid

An example for the formation of HEDP

Phosphonate
Phosphonates and phosphonic acids are organophosphorus compounds containing C-PO(OH)2 or
C-PO(OR)2 groups (where R=alkyl, aryl). Phosphonic acids and phosphonate salts are typically
white, nonvolatile solids that are poorly soluble in organic solvents, but soluble in water and
common alcohols. Many commercially important compounds are phosphonates, including
Glyphosate, the herbicide "Roundup", and Ethephon, a widely used plant growth regulator.
Bisphosphonates are popular drugs for treatment of osteoporosis.

Basic properties
Phophonates feature tetrahedral phosphorus centers. They are structurally closely related to (and
often prepared from) phosphorous acid.

Phosphonic acids and derivatives are chemically and structurally related to phosphorous acid.
Phosphonate salts are the result of deprotonation of phosphonic acids, which are diprotic acids:

RPO(OH)2 + NaOH H2O + RPO(OH)(ONa) (monosodium phosphonate)

RPO(OH)(ONa) + NaOH H2O + RPO(ONa)2 (disodium phosphonate)
Phosphonate esters are the result of condensation of phosphonic acids with alcohols.

Production
Several methods exist for the preparation of phosphonic acids and their salts.

From phosphonic acid

Most processes begin with phosphorous acid (aka phosphonic acid, H3PO3), exploiting its reactive
P-H bond.
Phosphonic acid can be alkylated under Mannich conditions to give aminomethylated
phosphonates, which are useful as complexants. One example is the industrial preparation of
nitrilotris (methylene phosphonic acid):
NH3 + 3 H3PO3 + 3 CH2O N(CH2PO3H2)3 + 3 H2O
Phosphonic acid also can be alkylated with acrylic acid derivatives to afford carboxyl
functionalized phosphonic acids. This reaction is a variant of the Michael addition:
CH2=CHCO2R + 3 H3PO3 (HO)2P(O)CH2CH2CO2R

Michaelis-Arbuzov reaction
Phosphonic esters are prepared using the MichaelisArbuzov reaction. For example, methyl iodide
catalyses the conversion of trimethylphosphite to the phosphonate ester dimethyl
methylphosphonate:
P(OMe)3 MePO(OMe)2
These esters can be hydrolysed to the acid (Me = methyl):
MePO(OMe)2 + H2O MePO(OH)2 + 2 MeOH
In the MichaelisBecker reaction, a hydrogen phosphonate diester is first deprotonated and the
resulting anion is alkylated.

From phosphorus trichloride

Vinylphosphonic acid can be prepared by the reaction of PCl3 and acetaldehyde:
PCl3 + CH3CHO CH3CH(O)PCl3+
This adduct reacts with acetic acid:
CH3CH(O)PCl3+ + 2 CH3CO2H CH3CH(Cl)PO(OH)2 + 2 CH3COCl
This chloride undergoes dehydrochlorination to afford the target:
CH3CH(Cl)PO(OH)2 CH2=CHPO(OH)2 + HCl

Bisphosphonates
Bisphosphonates were first synthesized in 1897 by Von Baeyer and Hofmann. An example of such
a bisphosphonate is HEDP (Etidronic acid or Didronel), that is 1-hydroxyethane-1,1-diphosphonic
acid, which is prepared from phosphorous acid and acetic anhydride:
2 H3PO3 + (CH3CO)2O CH3C(OH)(PO3H2)2 + CH3CO2H

Occurrence in nature
Phosphonates are one of the three sources of phosphate intake in biological cells. The other two
are inorganic phosphate and organophosphates.
The naturally-occurring phosphonate 2-aminoethylphosphonic acid was first identified in 1959 in
plants and many animals, where it is localized in membranes. Phosphonates are quite common
among different organisms, from prokaryotes to eubacteria and fungi, mollusks, insects and others.
They were first reported in natural soils by Newman and Tate (1980). The biological role of the
natural phosphonates is still poorly understood. Bis- or polyphosphonates have not been found to
occur naturally.

Uses
In 1998 the consumption of phosphonates was 56,000 tons worldwide - 40,000 tons in the US,
15,000 tons in Europe and less than 800 tons in Japan. The demand of phosphonates grows steadily
at 3% annually.

Metal chelants
Since the work of Schwarzenbach in 1949, phosphonic acids are known as effective chelating
agents. The introduction of an amine group into the molecule to obtain -NH2-C-PO(OH)2 increases
the metal binding abilities of the phosphonate. Examples for such compounds are NTMP, EDTMP
and DTPMP. These phosphonates are the structural analogues to the well-known
aminopolycarboxylate such as EDTA. The stability of the metal complexes increases with
increasing number of phosphonic acid groups. Phosphonates are highly water-soluble while the
phosphonic acids are only sparingly so.
Phosphonates are effective chelating agents. That is, they bind tightly to di- and trivalent metal
ions, which is useful in water softening. In this way, they prevent formation of insoluble
precipitates (scale). The binding of these ligands also suppresses the catalytic properties of metal
ions. They are stable under harsh conditions. For these reasons, an important industrial use of
phosphonates is in cooling waters, desalination systems, and in oil fields to inhibit scale formation.
Phosphonates are also regularly used in reverse osmosis systems as anti-scalants. Phosphonates in

cooling water systems also serve to control corrosion of iron and steel. In pulp and paper
manufacturing and in textile industry they serve as "peroxide bleach stabilizers," by chelating
metals that could inactivate the peroxide. In detergents they are used as a combination of chelating
agent, scale inhibitor, and bleach stabilizer. Phosphonates are also increasingly used in medicine
to treat disorders associated with bone formation and calcium metabolism. Furthermore they serve
as carriers for radionuclides in bone cancer treatments (see Samarium-153-ethylene diamine
tetramethylene phosphonate).

Medicine
In medicine, phosphonates and bisphosphonates are commonly used as inhibitors of enzymes
which utilize phosphates and diphosphates as substrates. Most notably, these enzymes include
those that produce the intermediates of cholesterol biosynthesis.

Biodegradation
In nature bacteria play a major role in the degradation of phosphonates. Due to the presence of
natural phosphonates in the environment, bacteria have evolved the ability to metabolize
phosphonates as nutrient sources. Some bacteria use phosphonates as a phosphorus source for
growth. Aminophosphonates can also be used as sole nitrogen source by some bacteria. The
polyphosphonates used in industry differ greatly from natural phosphonates such as 2aminoethylphosphonic acid, because they are much larger, carry a high negative charge and are
complexed with metals. Biodegradation tests with sludge from municipal sewage treatment plants
with HEDP and NTMP showed no indication for any degradation. An investigation of HEDP,
NTMP, EDTMP and DTPMP in standard biodegradation tests also failed to identify any
biodegradation. It was noted, however, that in some tests due to the high sludge to phosphonate
ratio, removal of the test substance from solution observed as loss of DOC was observed. This
factor was attributed to adsorption rather than biodegradation. However, bacterial strains capable
of degrading aminopolyphosphonates and HEDP under P-limited conditions have been isolated
from soils, lakes, wastewater, activated sludge and compost.
"No biodegradation of phosphonates during water treatment is observed but photodegradation of
the Fe(III)-complexes is rapid. Aminopolyphosphonates are also rapidly oxidized in the presence
of Mn(II) and oxygen and stable breakdown products are formed that have been detected in
wastewater. The lack of information about phosphonates in the environment is linked to analytical
problems of their determination at trace concentrations in natural waters. Phosphonates are present
mainly as Ca and Mg-complexes in natural waters and therefore do not affect metal speciation or
transport." Phosphonates interact strongly with some surfaces, which results in a significant
removal in technical and natural systems.

Phosphonate compounds
AMPA: Aminomethylphosphonic acid, degradation product of glyphosate
Vinylphosphonic acid: monomer
DMMP: Dimethyl methylphosphonate, one of the simplest phosphonate diesters
HEDP: 1-Hydroxyethylidene-1,1-diphosphonic acid, used in detergents, water treatment,
cosmetics and pharmaceuticals

ATMP: Amino tris(methylenephosphonic acid), chelating agent

EDTMP: Ethylenediamine tetra(methylene phosphonic acid), chelating agent
TDTMP: Tetramethylenediamine tetra(methylene phosphonic acid), chelating agent
HDTMP: Hexamethylenediamine tetra(methylene phosphonic acid), chelating agent
DTPMP: Diethylenetriamine penta(methylene phosphonic acid), chelating agent
PBTC: Phosphonobutane-tricarboxylic acid
PMIDA: N-(phosphonomethyl)iminodiacetic acid
CEPA: 2-carboxyethyl phosphonic acid
HPAA: 2-Hydroxyphosphonocarboxylic acid
AMP: Amino-tris-(methylene-phosphonic acid)
BPMG: N, N-Bis(phosphonomethyl)glycine
Glyphosate: a common agricultural herbicide
Foscarnet: for treatment of herpes
Perzinfotel: for treatment of stroke

Etidronic acid
Etidronic acid (INN) or 1-hydroxyethane 1,1-diphosphonic acid (HEDP) is a bisphosphonate used
in detergents, water treatment, cosmetics and pharmaceutical treatment.
An etidronate is a salt of etidronic acid, abbeviated MnHEDP (M: is a cation, n: number of M
maximum 4).

Chelating Agent and Anti-oxidant

Etidronic acid is a chelating agent and may be added to bind or, to some extent, counter the effects
of substances, such as calcium, iron or other metal ions, which may be discharged as a component
of grey wastewater and could conceivably contaminate groundwater supplies. As a phosphonate it
has corrosion inhibiting properties on unnalloyed steel. Etidronic acid also acts to retard
rancidification and oxidation of fatty acids.
HEDP and its salts are added to detergents and other cleaning agents to prevent the effects of hard
water. It is also used in peroxide bleaching to prevent degradation of peroxides by transition
metals.
Etidronic acid is listed as an ingredient of several cosmetic formulations where it is used for
suppressing radical formation, emulsion stabilser and viscosity control. While etidronic acid has
not been limited from inclusion in cosmetics and does have legitimate uses, it is recommended
that, as with most cosmetic products (particularly soaps), the product should be thoroughly rinsed
from the skin after use.
Etidronic acid is also included among swimming pool chemicals. It is used as a stain inhibitor to
prevent metal ions coming out of solution and staining the sides of swimming pools.

Systematic (IUPAC) name

(1-hydroxyethane 1,1-diphosphonic acid)

CAS Registry Number

2809-21-4

Formula

C2H8O7P2

Molecular mass

206.028 g/mol

Synthesis
Etidronic acid can be prepared by reaction of Phosphorus trichloride with acetic acid in a teritary
amine, or by reaction of an acetic acid/acetic anhydride mixture with phosphorous acid.

Uses
Pharmaceutical
Etidronic acid (Didronel) is a bisphosphonate used to strengthen bone, treat osteoporosis, and treat
Paget's disease of bone.
Bisphosphonates primarily reduce osteoclastic activity, which prevents bone resorption, and thus
moves the bone resorption/formation equilibrium toward the formation side and hence makes bone
stronger on the long run. Etidronate, unlike other bisphosphonates, also prevents bone
calcification. For this reason, other bisphosphonates, like alendronate, are preferred when fighting
osteoporosis. To prevent bone resorption without affecting too much bone calcification, etidronate
must be administered only for a short time once in a while, for example for two weeks every 3
months. When given on a continuous basis, say every day, etidronate will altogether prevent bone
calcification. This effect may be useful and etidronate is in fact used this way to fight heterotopic
ossification. But in the long run, if used on a continuous basis, it will cause osteomalacia.

Chemical
HEDP is used as scale and corrosion inhibition in circulating cool water system, oil field and lowpressure boilers in fields such as electric power, chemical industry, metallurgy, fertilizer, etc. In
light woven industry, HEDP is used as detergent for metal and nonmetal. In dyeing industry,
HEDP is used as peroxide stabilizer and dye-fixing agent; In non-cyanide electroplating, HEDP is
used as chelating agent. The dosage of 110 mg/L is preferred as scale inhibitor, 1050 mg/L as
corrosion inhibitor, and 10002000 mg/L as detergent. Usually, HEDP is used together with
polycarboxylic acid.

Properties
HEDP is an organophosphoric acid corrosion inhibitor. It can chelate with Fe, Cu, and Zn etc.
metal ions and form stable complex compound. It can dissolve the oxidized materials on these
metals surfaces. HEDP has good chemical stability under high pH value, hard to be hydrolyzed,
and hard to be decomposed under ordinary light and heat conditions. HEDP can react with metal
ions in water system to form hexa-element chelating complex, with calcium ion in particular.
Therefore, HEDP has good antiscale and visible threshold effects.

Process for manufacturing 1-hydroxyethane 1,1-diphos-phonic acid

A process for manufacturing 1-hydroxyalkylidene-1,1-diphosphonic Acid (HADP) by introducing
phosphorus trihalide (PX3) into a reactor containing aqueous acid of the formula RCOOH at a
temperature of 60-200 C. and a pressure of 15-150 psig. Water is added to hydrolyze the
intermediate formed to obtain HEDP.
Various processes have been described for producing HEDP. They all, however, suffer from
certain disadvantages.
Initial process used for HEDP manufacturing process is difficult to control, and can result in
formation of explosive compounds. In that process, PCl3 is first reacted with glacial acetic acid at
a temperature of 60-70 C. to form phosphorous acid and acetyl chloride intermediates which
slowly react with each other. Gaseous acetyl chloride and PCl3 evolve in this step. Because of this,
the process requires strictly controlled feeding of both the PCl3 and acetic acid to maintain the
correct hydroxyl balance and to prevent the formation of explosive Lower Oxides Of Phosphorus
(LOOP). The next stage involves a long and very difficult to control heating step, in which gaseous
acetyl chloride and HCl evolve. Acetic anhydride, which is very expensive, must be added to
complete the reaction.
The further process improves on that of initial process, but suffers from serious safety hazards.
PCl3 is first fed into a reactor containing glacial acetic acid at a temperature of above 100 C. At
this temperature, reaction intermediates (phosphorous acid and acetyl chloride) react with each
other almost instantaneously, forming a mass that separates into two phases. The top phase
contains primarily acetic acid, with acetyl chloride. The bottom phase contains primarily
acetylated HEDP, with phosphorous acid (<5%) and acetic acid. Under atmospheric pressure and
a temperature of >100 C., the acetyl chloride is either reacted to form HEDP, or lost overhead
and condensed into an acetyl chloride receiver. Because glacial acetic acid is used, each mole of
PCl3 generates one mole of HCl, and two moles of excess acetyl chloride which must be separated
from the HCl and condensed. Extreme caution must be exercised in handling the acetyl chloride
because of its toxicity, volatility, combustibility, and reactivity with water and alkalies.
Furthermore, because the reaction temperature is high, HCl gas and unreacted acetyl chloride leave
the reactor along with entrained PCl3 and acetic acid. A very large overhead condenser is required
to handle this large volume of gases. Also, the entrained PCl3, and phosphorous acid produced by
earlier entrained PCl3, can react to generate explosive LOOP. In the final step of the process,
intermediates of HEDP are hydrolyzed and vacuum stripped (at 10-50 mmHg and 80-120 C.) to
remove acetic acid.
The present invention provides a process for making 1-hydroxyalkylidene-1,1-diphosphonic acid
(HADP) that is economical, safe, and forms little waste product. The process includes the steps of
a) reacting PX3 and aqueous R-COOH at a temperature of between 60 C. and 200 C. and a
pressure between 15 and 150 psig, where X is a halogen and R is an alkyl group having from
1 to 18 carbon atoms; and
b) hydrolyzing the product of step (a) with water to form HADP.

In the formula shown above, R is preferably from 1 to 4 carbon atoms, and most preferably R is
CH3, resulting in formation of HEDP. The overall reaction which takes place when carrying out
the preferred steps of the invention to produce HEDP is shown below.
While PCl3 is used in the preferred embodiment, it is understood that other halides of the formula
PX3 can be substituted.
The process can be started by charging water and acetic acid into a batch reactor. After heating to
reaction temperature, PCl3 is metered in over a period of from 1 to 10 hours, preferably
continuously over a period of from 3 to 8 hours. The reactants are agitated and the reaction
temperature is maintained between 60 C. and 200 C., preferably between 80 C. and 150 C.,
most preferably between 100 C. and 120 C. The reactor pressure is maintained at between 15
and 150 psig, preferably between 20 and 110 psig, and most preferably between 30 and 80 psig.
Maintaining a high reactor pressure raises the boiling points of acetic acid and PCl 3, thereby
reducing the amount of gaseous acetic acid and PCl3 that is given off. Formation of LOOP is
thereby prevented. The high reactor pressure also retains more acetyl chloride in the reaction
mixture, eliminating the need for added acetic anhydride.
Acetyl chloride that is initially formed subsequently reacts to form HEDP. HCl exits the reactor in
substantial amounts along with a small amount of the acetyl chloride. A water cooled (less than
30 C.) demister can be used to reduce acetyl chloride entrainment. The acetyl chloride can also
be absorbed in a small scrubber, recovered as acetic acid, and then recharged into the next batch
reaction. This keeps the HCl scrubber free of acetic acid contamination.
This provides sufficient hydroxyl groups for PCl3 to react with to form H3PO3. In the absence of
sufficient hydroxyl groups, PCl3 reacts with H3PO3 to form explosive LOOP.
At the end of the PCl3 addition, the reactor mass become turbid and separates into two phases when
agitation is stopped. Two phases form because acetylated HEDP is immiscible with acetic acid.
After the PCl3 is completely added, the reaction mass is preferably maintained at the reaction
temperature for another hour, after which the reactor is slowly vented.
Hydrolysis is carried out by feeding water or steam into the reactor at a temperature of between
60 C. and 200 C., preferably between 110 C. and 140 C., over a period of between 5 minutes
and 6 hours. Feeding over a period greater than 30 minutes is preferred, because the hydrolysis
reaction is highly exothermic. The preferred mode of feeding is by a subsurface steam sparge. The
molar ratio of PCl3 to water is preferably 1:0.8-2.5, more preferably 1:1-2, and most preferably
about 1:1.
The excess acetic acid that remains in the reaction mass can then be steam stripped. This is
preferably done under a vacuum (100-600 mmHg absolute pressure) at between about 100 C. and
200 C., preferably between about 100 C. and 150 C., most preferably between about 110 C.
and 130 C. Steam or hot water is fed at a rate of about 5% and 20%, preferably between about
10% and 15%, of the total reactor charge weight over a period of between about 0.5 and 4 hours,

preferably between about 1.5 and 3 hours. Applying a slow steam feed and a moderate vacuum
allow reuse of >95% of the acetic acid recovered in the steam stripping process. These parameters
also avoid high viscosity and high skin temperature, which degrade the quality of the final product.
This invention is illustrated by the following example, which is intended to exemplify the
invention, not to limit its scope.

An example for the formation of HEDP is given as follows

123.1 lbs. of glacial acetic acid and 31.7 lbs. of water were charged into a stirred reaction vessel
equipped with a water jacket, pressure control valve (release pressure set at 70 psig), reflux
condenser and stripping condenser. The batch was heated to 115 C. When the reactor temperature
reached 90 C., PCl3 was pumped at 0.75 lbs./min. to feed 90 lbs of PCl3 below the surface of the
reaction mixture over 2.0 hrs. The reactor temperature was maintained at 1155 C.
The PCl3 pump rate was then lowered to 0.50 lbs./min., to feed 59.7 lbs. of PCl3 into the reactor
over an additional 2.0 hrs. The reactor temperature was maintained at 1155 C. Thus, a total of
149.7 lbs of PCl3 was fed into the reactor over 4.0 hrs.
After the PCl3 addition was completed, the reaction mixture was maintained at 115 C. for an
additional hour. The reactor was then sampled for the presence of unreacted phosphorous acid
intermediate to determine whether the reaction was complete. When it was determined that the
reaction was complete, the pressure was gradually reduced to 5 psi (or lower) by venting over 30
min. When the venting process was complete, the reactor was sealed and 5.7 lbs. of hydrolysis
water was fed through a subsurface dip tube at a rate of 0.19 lbs./min. over 30 minutes. The
addition rate was controlled to keep the reactor temperature below 130 C. An additional 13.9 lbs.
of hydrolysis water was fed over 30 minutes (i.e., a rate of 0.46 lbs./min.), while the reactor
temperature was again maintained at 1305 C.
After water addition was completed, the reactor was maintained at 130 C.5 C. for an additional
hour. Then, maintaining the same temperature, pressure was reduced over 30 minutes to reach a
final vacuum of 300 mmHg (abs), the rate being controlled to prevent foaming of the reaction
mixture. At 500 mmHg (abs), hot water was pumped into the reactor through a dip tube at a feed
rate of 18 lbs./hour. Distillate was then collected into a first acetic acid receiver for recycling. The
distillate was monitored for its concentration of acetic acid. When the acetic acid in the distillate
reached a concentration of less than 10 wt. % the distillate was collected in a second receiver.
When the acetic acid concentration in the distillate leveled off to below 5 wt. %, the reactor was
sampled for percent acetic acid. When residual acetic acid in the reactor was less than 0.3 wt. %,
the steam was stopped, the reactor sealed, and nitrogen added to break the vacuum. 56 lbs. of water
was pumped through a dip tube and the reactor was cooled down to 50 C.